N-halamines compounds as multifunctional additives

ABSTRACT

The present invention is a composition and method for making and using a rechargeable multifunctional additive that reduce the formation of biofilms on a surface, the additive can also remain photo and thermally stable by synthesizing one or more N-halamine compounds and adding one or more N-halamine biocidal compounds to a target material prior, during or after the target material is made. The resultant material can be used directly to provide antimicrobial functions and control biofilm formation, or the material can be further processed into an article.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application Ser.No. 60/707,331, filed Aug. 11, 2005, the contents of which isincorporated by reference herein in its entirety.

TECHNICAL FIELD OF THE INVENTION

The present invention relates in general to the field of multifunctionaladditives of materials, and more particularly, to the chemicallyN-halamines as additives of material to provide antimicrobial,anti-biofilm, and/or photo and thermal stabilities.

BACKGROUND OF THE INVENTION

Without limiting the scope of the invention, its background is describedin connection with additive compounds that act as multifunctionalmaterials, as an example.

Contamination of materials by microorganisms such as pathogenicbacteria, molds, fungi and viruses is of great concern in the medicalindustry, the food and restaurant industries, as well as in consumerproducts as a result of the potential for the spread of infections.Survival of microorganisms on various materials and transfer of thesemicroorganisms between materials, animals and humans has beendemonstrated, and it is widely accepted that microorganism-contaminatedmaterials can be elements in cross-infections and transmission ofdiseases caused by microorganisms. Furthermore, the structure andcharacteristics of biofilms allow the growth and proliferation ofcontaminants and make the cleaning and removal of pathogenic bacteria,molds, fungi and viruses extremely difficult.

Microorganisms have strong abilities to survive on ordinary materialsand can stay alive for as long as 90 days. These microorganisms canfurther develop into firmly attached biofilms. A biofilm is anaccumulation of microorganisms (e.g., bacteria, fungi, and/or protozoa,with associated bacteriophages and other viruses) embedded in apolysaccharide matrix and adherent to solid biologic or non-biologicsurface.

Biofilms are remarkably difficult to treat with antimicrobials, whichmay be readily inactivated or fail to penetrate into the biofilm. Inaddition, microorganisms within biofilms have increased (e.g., up to1000-fold higher) resistance to antimicrobial compounds, even thoughthese same microorganisms are sensitive to these agents if grown underplanktonic conditions. Furthermore, microorganisms express new, andsometimes more virulent phenotypes when grown within a biofilm. Suchphenotypes may not have been detected in the past because the organismswere grown on rich nutrient media under planktonic conditions. Thegrowth conditions are quite different particularly in the depths ofbiofilms, where nutrients and oxygen are usually limited, and wasteproducts from neighbors can be toxic. In short, microorganisms found atthe bottom of the biofilm look and act different from microorganismslocated at the surface.

Biofilms represent a serious problem in environmental, medical andindustrial fields. Additionally, biofilms increase the opportunity forgene transfer between/among microorganisms allowing microorganismsresistant to antimicrobials or chemical biocides to transfer the genesfor resistance to neighboring susceptible microorganisms. Gene transfercan convert a previous avirulent commensal organism into a highlyvirulent pathogen. Certain species of microorganisms communicate witheach other within the biofilm. As their density increases, the organismssecrete low molecular weight molecules that signal when the populationhas reached a critical threshold, e.g., quorum sensing, is responsiblefor the expression of virulence factors.

Microorganisms embedded within biofilms are resistant to bothimmunological and non-specific defense mechanisms of the body. Contactwith a solid surface triggers the expression of a panel of bacterialenzymes, which catalyze the formation of sticky polysaccharides thatpromote colonization and protection. The structure of biofilms is suchthat immune responses may be directed only at those antigens found onthe outer surface of the biofilm, and antibodies and other serum orsalivary proteins often fail to penetrate into the biofilm. In addition,phagocytes are unable to effectively engulf a bacterium growing within acomplex polysaccharide matrix attached to a solid surface. This causesthe phagocyte to release large amounts of pro-inflammatory enzymes andcytokines, leading to inflammation and destruction of nearby tissues.Because biofilm formation is triggered by the survival and adherence ofmicrobes onto different materials, the introduction of biocidalfunctions into the target materials can be an effective method toinactivate the microbes and thus control biofilms.

In addition to the medical and healthcare fields, the food andrestaurant industries, as well as in consumer are increasingly concernedwith microbial contamination, e.g., food contact between contaminatedarticles. Multiple outbreaks of food borne bacterium such as E. coli,have made people increasingly conscious of methods to control the spreadof such bacterium. Food contact materials such as cutting boards,sponges, towels and the like have long been suspected to be vectors forthe spread of food borne microorganisms. Therefore, the induction ofbiocidal properties should be an effective feature of healthcare andhygienic-use applications.

The foregoing problems have been recognized for many years and whilenumerous solutions have been proposed, none of them adequately addressall of the problems in a single device, e.g., effectiveness against manyforms of bacteria, toxicity, stability and rechargeability.

SUMMARY OF THE INVENTION

The present inventors recognized a need for rechargeable additives thatact as broad-spectrum antimicrobial and biofilm-controlling agents,which may also provide other desirable functions, such as photo andthermal stabilization, reducing leaching of organic contaminants intothe medium to be disinfected and maintaining a low concentration of freehalogen in the medium.

The present invention uses N-halamine-based compounds to providebiocidal and biofilm-controlling functions. An N-halamine is a compoundcontaining one or more nitrogen-halogen covalent bonds that is normallyformed by the chlorination or bormination of cyclic imide, amide oramine groups. One of the properties of N-halamines is that when microbescome into contact with the N—X structures (e.g., X is Cl or Br), ahalogen exchange reaction occurs, resulting in the expiration of themicroorganisms. The process consumes halogens, but the consumed halogenscan be recharged by another halogen treatment. Thus, N-halamines aregenerally regarded as rechargeable batteries of covalently boundhalogens. N-halamines are much more stable and safer to use thanhypochlorite bleach, yet have a similar antimicrobial efficacy. In thecurrent invention, imide-, amide-, melamine- and amine-based N-halaminesor their combinations are used as the additives.

The present invention provides a method of making a rechargeableantimicrobial and biofilm-controlling material by synthesizing one ormore N-halamine biocidal compounds and adding one or more N-halaminebiocidal compounds to a target material. The target material is useddirectly, or processed into the desired articles, coatings, paints,medical devices and so forth.

The present invention also provides a method of making an antimicrobialand biofilm-controlling material by adding one or more precursors of theN-halamine biocidal compounds to a target materials and/or processingone the target material into an article. Then one or more halogensources are added to the material or article, wherein the one or moreprecursors of the N-halamine biocidal compounds are transformed into oneor more active N-halamine biocidal compounds.

The present invention provides a method of reducing the formation ofbiofilms on a surface by synthesizing one or more N-halamine biocidalcompounds and adding the one or more N-halamine biocidal compounds to atarget material. The target material having one or more N-halaminebiocidal compounds is then placed into contact with the surface, wherebythe formation of biofilms is reduced.

The present invention includes a self-decontaminating monomeric orpolymeric N-halamine biocidal composition having the formula I, II, III,IV, V, VI, VII, VIII or combinations thereof, wherein X, X¹, X², X³ andX⁴ are individually a Hydrogen or a halogen; R¹ to R¹⁰ are independentlyhydrogens, halogens, one or more C₁ to C₄₀ alkyl, C₁ to C₄₀ alkylene, C₁to C₄₀ alkenyl, C₁ to C₄₀ alkynyl, C₁ to C₄₀ aryl, C¹, to C₃₀ alkoxy, C₁to C₄₀ alkylcarbonyl, C₁ to C₄₀ alkylcarboxyl, C₁ to C₄₀ amido, C₁ toC₄₀ carboxyl, or combinations thereof.

For example, the present invention provides a rechargeable N-halaminebiocidal compound including3-substituted-1-N-halo-5,5-disubstituted-hydantoin;3,3′-bissubstituted-1,1′-N-halo-5,5,5′5′-substituted-2,2′,4,4′-imidazolidinedione;1,3,8-Triaza-3-substituted-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decane;3,3′disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,8,8′N-halo-2,4-dione;8,8′-disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,3,3′N-halo-2,4-dione;poly(vinyl chloride-co-3-vinyl-N-halo-5,5-disubstituted hydantoin);poly(vinylchloride-co-3-vinyl-1,3,8-Triaza-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decane).

Furthermore, biofilm controlling materials which are stable to photo andthermal treatment may be made by mixing a sterically hindered aminelight stabilizer with a source of halide atoms to form a stericallyhindered N-halo-amine and forming a material in the presence of thesterically hindered N-halo-amine.

The present invention also includes a method of recharging abiofilm-controlling material, which are stable to photo and thermalchallenge by exposing a sterically hindered amine stabilizer to a sourceof halide atoms.

The present invention includes a method of making a biofilm controllingmaterial which is photo and thermal treatment stable by forming anN-halamine biocidal compound which is added to one or more halogensources, wherein the N-halamine biocidal compound is transformed intoone or more active N-halamine biocidal compounds.

Another example of the present invention includes a hinderedN-halo-amine, which can provide biofilm-controlling as well as photo andthermal stabilizing functions. Examples of these hindered N-halo-aminesinclude, but not limit to,Bis(N—X-2,2,6,6-tetramethyl-4-piperidyl)sebacate;Poly[[6-[(1,1,3,3-tetramethylbutyl)amino]-s-triazine-2,4-diyl]-N—X-[(2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene-[(2,2,6,6-tetramethyl-4-piperidylimino]];N—X-[(4-piperidyl alkyl formate];Poly[(6-morpholino-s-triazine-2,4-diyl)-N—X-[2,2,6,6-tetramethyl-4-piperidyl]imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]];3-Dodecyl-N-chloro-(2,2,6,6-tetramethyl-4-piperidinyl)succinimide;2,2,4,4-Tetramethyl-N—X-7-oxa-3,20-diazadispiro[5.1.11.2]-heneicosan-21-one;D-Glucitol,1,3:2,4-bis-O-(N-chloro-2,2,6,6-tetramethyl-4-piperidinylidene);1,1′-ethylenebis(N—X-3,3,5,5-tetramethyl-piperazinone);N—X-2,2,4,4-tetramethyl-7-oxa-20-(oxiranylmethyl)-3,20-diazadispiro[5.1.11.2]henicosan-21-one;1,2,3,4-Butanetetracarboxylic acid, polymer withβ,β,β′,β′-tetramethyl-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diethanol,N—X-2,2,6,6-tetramethyl-4-piperidinyl ester;Poly[oxy[methyl[3-[N—X-(2,2,6,6-tetramethyl-4-piperidinyl)-oxy]propyl]silylene]];1,1′,1″-[1,3,5-Triazine-2,4-6-triyltris[(cyclohexylimino)ethylene]]tris(N-chloro-3,3,5,5-tetramethyl-piperazinone);and mixtures and combinations thereof, wherein X is Cl, Br orcombinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the features and advantages of thepresent invention, reference is now made to the detailed description ofthe invention along with the accompanying figures and in which:

FIG. 1 is a schematic of general chemical structures of the N-halaminecompounds;

FIG. 2 is a scheme illustrating one method of synthesis of3-alkyl-5,5-dimethylhydantoins;

FIG. 3 is an IR spectra of DMH, BD, DDMH and Cl-DDMH;

FIG. 4 shows the proton NMR spectra of BD, DMH, DDMH and Cl-DDMH;

FIG. 5 is a UV spectrum of the N—H→N—Cl transformation;

FIG. 6 illustrates DSC curves showing DCSDMH and Cl-DCSDMH;

FIGS. 7A and 7B are graphs of the cells killed using 500 ppm of activechlorine;

FIGS. 8A and 8B are graphs of the cells killed using 1000 ppm of activechlorine;

FIG. 9 is a ¹H NMR spectra to confirm the chemical structure of Cl-BTMP;

FIG. 10 is a ¹³C NMR spectra to confirm the chemical structure ofCl-BTMP;

FIG. 11 is a UV/VIS spectrum to confirm the chemical structure ofCl-BTMP;

FIGS. 12A and 12B are graphs of the carbonyl index of the film samplesin photo and thermal stability studies;

FIGS. 13A, 13B and 13C are FT-IR spectra of the samples after differentperiods of UV irradiation;

FIGS. 14A, 14B and 14C are FT-IR spectra of the samples after differentperiods of thermal aging at 130° C.;

FIGS. 15A, 15B and 15C are FT-IR spectra of the samples after differentperiods of thermal aging at 130° C.;

FIG. 16 is a graph of the chlorine content of Cl-BTMP after differentcycles of re-chlorination treatments; and

FIG. 17 is a synthesis schematic of the N-halamine compounds.

DETAILED DESCRIPTION OF THE INVENTION

While the making and using of various embodiments of the presentinvention are discussed in detail below, it should be appreciated thatthe present invention provides many applicable inventive concepts thatcan be embodied in a wide variety of specific contexts. The terminologyused and specific embodiments discussed herein are merely illustrativeof specific ways to make and use the invention and do not delimit thescope of the invention.

To facilitate the understanding of this invention, a number of terms aredefined below. Terms defined herein have meanings as commonly understoodby a person of ordinary skill in the areas relevant to the presentinvention. Terms such as “a”, “an” and “the” are not intended to referto only a singular entity, but include the general class of which aspecific example may be used for illustration. The terminology herein isused to describe specific embodiments of the invention, but their usagedoes not delimit the invention, except as outlined in the claims.

The terms “antimicrobial compound,” “antimicrobial,” “microbicidal,”“biocide,” “biocidal” and “halogenated amide antimicrobial” are usedinterchangeably herein and refer to halogenated amides that function asbiocides to kill at least some types of microorganisms, or to inhibitthe growth or reproduction of at least some types of microorganisms(i.e., compounds which inhibit the growth of, or kills, microorganismssuch as bacteria, molds, slimes, fungi, etc.).

As used herein, the term “alkyl” denotes branched or unbranchedhydrocarbon chains, preferably having about 1 to about 10 carbons, suchas, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,tert-butyl, octa-decyl and 2-methylpentyl. These groups can beoptionally substituted with one or more functional groups which areattached commonly to such chains, such as, hydroxyl, bromo, fluoro,chloro, iodo, mercapto or thio, cyano, alkylthio, heterocyclyl, aryl,heteroaryl, carboxyl, carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl,amido, and the like to form alkyl groups such as trifluoro methyl,3-hydroxyhexyl, 2-carboxypropyl, 2-fluoroethyl, carboxymethyl,cyanobutyl and the like.

The term “alkylene” refers to a divalent alkyl group as defined above,such as methylene (—CH₂—), propylene (—CH2 CH₂ CH₂—), chloroethylene(—CHClCH₂—), 2-thiobutene—CH₂ CH(SH)CH₂ CH₂,1-bromo-3-hydroxyl-4-methylpentene (—CHBrCH₂ CH(OH)CH(CH₃)CH₂—), and thelike.

As used herein, the term “alkenyl” denotes branched or unbranchedhydrocarbon chains containing one or more carbon-carbon double bonds.

The term “alkynyl” refers to branched or unbranched hydrocarbon chainscontaining one or more carbon-carbon triple bonds.

As used herein, the term “aryl” denotes a chain of carbon atoms whichform at least one aromatic ring having between about 4-14 carbon atoms,such as phenyl, naphthyl, and the like, and which may be substitutedwith one or more functional groups which are attached commonly to suchchains, such as hydroxyl, bromo, fluoro, chloro, iodo, mercapto or thio,cyano, cyanoamido, alkylthio, heterocycle, aryl, heteroaryl, carboxyl,carbalkoyl, alkyl, alkenyl, nitro, amino, alkoxyl, amido, and the liketo form aryl groups such as biphenyl, iodobiphenyl, methoxybiphenyl,anthryl, bromophenyl, iodophenyl, chlorophenyl, hydroxyphenyl,methoxyphenyl, formylphenyl, acetylphenyl, trifluoromethylthiophenyl,trifluoromethoxyphenyl, alkylthiophenyl, trialkylammoniumphenyl,amidophenyl, thiazolylphenyl, oxazolylphenyl, imidazolylphenyl,imidazolylmethylphenyl, and the like.

The term “alkoxy” denotes—OR—, wherein R is alkyl. The term“alkylcarbonyl” denote an alkyl group as defined above substituted witha C(O) group, for example, CH₃C(O)—, CH₃CH₂C(O)—, etc. As used herein,the term “alkylcarboxyl” denote an alkyl group as defined abovesubsituted with a C(O)O group, for example, CH₃C(O)O—, CH₃ CH₂C(O)O—,etc. As used herein, the term “amido” denotes an amide linkage: —C(O)NHR(wherein R is hydrogen or alkyl). The term “amino” denotes an aminelinkage: —NR—, wherein R is hydrogen or alkyl. The term “carbocycle”means a cyclic hydrocarbon chain having about 5 to about 8 ring carbonssuch as cyclopentyl, cylcohexyl, etc. These groups can be optionallysubstituted with one or more functional groups as defined under “alkyl”above.

As used herein, the term “carboxyl” denotes—C(O)O—, and the term“carbonyl” denotes—C(O)—. The term “cycloalkyl” signifies a saturated,cyclic hydrocarbon group with 3-8, preferably 3-6 carbon atoms, i.e.cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl and the like.

As used herein, the terms “N-halamines,” “Heterocyclic N-halamine” and“cyclic N-halamine unit” denotes a class of chemicals that contain ahalogen bound to a nitrogen atom, where the nitrogen is a member of aring, along with carbon atoms. When bound to the nitrogen, the halogenis in a stable form and retains the ability to interact with targets onthe surfaces of bacteria and other microbes. The presence of the halogenrenders it biocidal. For example, heterocyclic, monocyclic compoundshaving 4 to 7-membered ring, wherein at least 3 members of the ring arecarbon, and from 1 to 3 members of the ring are nitrogen heteroatom, andfrom 0 to 1 member of the ring is oxygen heteroatom. Additionally, theremay be from 0 to 2 carbon members comprise a carbonyl group, and whereinat least 1 to 3 nitrogen atoms are substituted with a hydroxyalkylgroup, such as—CH₂ OH, or an alkoxyalkyl group, such as—CH₂ OCH₃. Inaddition, the ring members can be further substituted with alkyl groups,such as methyl, ethyl, etc.

The term “halogen” includes chlorine, fluorine, bromine and mixturesthereof. The term “heteroaryl” refers to an aromatic mono- or bicyclicradical having 5 to 10, preferably 5 to 6 ring atoms, containing one tothree heteroatoms, preferably one heteroatom, e.g. independentlyselected from nitrogen, oxygen or sulfur. Examples of heteroaryl groupsare thiophenyl, isoxazolyl, thiazolyl, piperidinyl, pyridinyl, pyrrolyl,imidazolyl, tetrazolyl, preferably pyridinyl, isoxazolyl or thiazolyl.Optionally, the heteroaryl group can be mono-, di- or tri-substituted,independently, with phenyl, alkyl, alkylcarbonyl, alkoxycarbonyl,hydroxy, amino, alkylamino, dialkylamino, carboxy, alkoxycarbonylalkyl,preferably alkyl.

The term “heterocycle” means a straight chain or ring system that maycontain from zero to four heteroatoms selected from N, O and S, whereinthe nitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. These groups can be optionallysubstituted with one or more functional groups as defined under “alkyl”above.

As used herein, the terms, “polymer” and “copolymer” are at times usedinterchangeably to mean a cyclic amine or N-halamine unit joined by alinkage to a second cyclic amine or N-halamine unit is not meant to belimiting as to the number of cyclic amine or N-halamine units in apolymer, e.g., two or more cyclic amine or N-halamine units, and thenumber of units in any given polymer can vary according to the useintended for the polymer. Other polymers include flexible PVC,polyurethanes, polyolefins, thermoplastic polyolefins, thermoplasticelastomers, rubber, silicones, polyester; however the skilled artisanwill recognize other polymers may be used. The polymer may be a randomcopolymer contains a random arrangement of the multiple monomers. Thepolymer may be a block copolymer contains blocks of monomers of the sametype. The polymer may also be a graft copolymer contains a main chainpolymer consisting of one type of monomer with branches made up of othermonomers. For example, the polymer can comprise 2, 3, 4, 5, 6, 7, 8, 9,10, 20, 25, 30, 40, 50, 75, 100, 150, 200, 250, 500, 1000, and so forth,units.

The present invention provides a method of making a rechargeableantimicrobial and biofilm-controlling material by synthesizing one ormore N-halamine biocidal compounds and adding one or more N-halaminebiocidal compounds to a target material. The target material is useddirectly, or processed into the desired articles, coatings, paints,medical devices and so forth.

The present invention also provides a method of making an antimicrobialand biofilm-controlling material by adding one or more precursors of theN-halamine biocidal compounds to a target materials and/or processingone the target material into an article. Then one or more halogensources are added to the material or article, wherein the one or moreprecursors of the N-halamine biocidal compounds are transformed into oneor more active N-halamine biocidal compounds.

Generally, the one or more N-halamine biocidal compounds include one ormore 4 to 7 membered rings and one or more nitrogen heteroatoms.Specific examples include comprises3-substituted-1-N-halo-5,5-disubstituted-hydantoin;3,3′-bissubstituted-1,1′-N-halo-5,5,5′5′-substituted-2,2′,4,4′-imidazolidinedione;1,3,8-Triaza-3-substituted-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decane;3,3′-disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,8,8′N-halo-2,4-dione;8,8′-disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,3,3′N-halo-2,4-dione;Vinyl chloride-co-3-vinyl-N-halo-5,5-disubstituted hydantoin; Vinylchloride-co-3-vinyl-1,3,8-Triaza-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decaneand combinations thereof. However, the skilled artisan will recognizethat the 4 to 7 membered rings with one or more nitrogen heteroatoms maybe substituted with one or more alkyl groups, alkylene groups, alkenylgroups, alkynyl groups, aryl groups, alkoxy groups, alkylcarbonylgroups, alkylcarboxyl groups, amido groups, carboxyl groups, halogens,hydrogens or combinations thereof.

Additionally, the N-halamine biocidal compound may be in communicationwith or bonded to, either covalently or ionically, one or more halogens.In addition the presence of halogen may be replenished whenconcentrations are low doe to activity, diffusion, reactivity, redoxreactions through the treatment a hypohalogenic solution, e.g.,hypochlorite or hypoborite solution.

The N-halamine biocidal compounds may be integrated into a polymer asstabilization agents, polymeric materials, copolymers, additives or thelike. The target material may be a polymer in the form of plastics,cellulose, rubbers, fibers, woods, paints, coatings.

The monomeric and polymeric N-halamine compounds of the presentinvention for antimicrobial and anti-biofilm applications include theeight (8) basic formulas, as shown in FIG. 1. In these formulas, the N—X(e.g., X is a halogen) structures are stable N-halamines. Thesecompounds can provide potent, durable and rechargeable biocidalfunctions against bacteria, fungus, yeast, virus and spores. The basicformulas illustrated in FIG. 1 may be substituted with one or morefunctional groups at one or more of the R positions, e.g., R¹-R¹⁰. Theskilled artisan will recognize that the R substitution may take manyforms, e.g., the R group may independently be an alkyl group, analkylene group, an alkenyl group, an alkynyl group, an aryl group, analkoxy group, an alkylcarbonyl group, an alkylcarboxyl group, an amidogroup, a carboxyl group or a halogen. Further more the R group may besubstituted with one or more alkyl groups, alkylene groups, alkenylgroups, alkynyl groups, aryl groups, alkoxy groups, alkylcarbonylgroups, alkylcarboxyl groups, amido groups, carboxyl groups or halogens.

In one example of the synthesis of the N-halamine compounds with thegeneral formula 1 as shown in FIG. 1, 5,5-dimethylhydantion (DMH) waspurchased from Acros Organics, 1-bromoethane (BE), 1-bromobutane (BB),1-bromohexane (BH), 1-bromododecane (BD) and 1-bromooctadecane (BOD)were provided by ALDRICH, 1-bromodocosane (BDCS) by Tokyo Kasei KogyoCo. LTD. Trichloroisocyanuric acid (99%, TCCA) used as a chlorinatingagent was obtained from Acros Organics. All chemicals were used withoutfurther purification. The synthesis process is illustrated below.

To about 30 mL of methanol solution containing 0.025 mol (e.g., 3.20 g)of DMH was added to about 0.03 mol (e.g., 1.68 g) of potassiumhydroxide. The mixture was heated and kept at about 50° C. for about 30minutes After evaporation of the methanol and the water produced in thereaction under reduced pressure, the solid potassium salt of DMH wasdried in a vacuum oven at about 60° C. for three days to form theanhydrous potassium salt. The dry salt was then mixed with about 100 mLof N,N-dimethylformamide (DMF) at about 95° C. for about 10 minutesunder constant stirring, and about 0.025 mol of 1-brominated hydrocarbonwas added, and the solution was reacting for about 2 hours.

3-ethyl-5,5-dimethylhydantoin (EDMH). After reaction, the solid in thereaction solution was filtered off and the DMF solvent in the filtratewas removed by distillation under reduced pressure. The residualsubstance was recrystallized from distilled water. 3.65 grams of EDMHwas received as a white powder, yield: 93.5%.

3-butyl-5,5-dimethylhydantoin (BDMH). After reaction, the solid in thereaction solution was filtered off and the DMF solvent in the filtratewas removed by distillation under reduced pressure. The residualsubstance was isolated with chloroform. After evaporation of chloroform,3.75 grams of BDMH was obtained as transparent viscous liquid, yield:81.5%.

3-hexyl-5,5-dimethylhydantoin (HDMH). 3.50 grams of HDMH was obtained astransparent viscous liquid following the same procedure described inBDMH, yield: 66.0%.

3-dodecyl-5,5-dimethylhydantoin (DDMH). 6.23 grams of BD. Afterreaction, the solid in the reaction solution was filtered off and thefiltrate was cooled to 0° C. The precipitate was isolated by filtrationand recrystallized from methanol. 7.10 grams of DDMH was obtained as awhite powder, yield: 95.9%.

3-octadecyl-5,5-dimethylhydantoin (ODDMH). 8.34 grams of BOD. 8.20 gramsof ODDMH was obtained as a white powder following the same proceduredescribed in DDMH, yield: 86.2%.

3-docosanyl-5,5-dimethylhydantoin (DCSDMH). 9.74 grams of BDCS. 10.20grams of DCSDMH was obtained as a white powder following the sameprocedure described in DDMH, yield: 93.4%.

General procedure for the synthesis of chlorinated3-alkyl-5,5-dimethylhydantoin. 3-alkyl-5,5-dimethylhydantoin andtrichloroisocyanuric acid (e.g., TCCA, molar ratio 1:3) were dissolvedin acetone. The solution was vigorously stirred for 30 minutes at roomtemperature and then the acetone solvent was evaporated. Hexane wasadded to the mixtures and the insoluble solid was filtered off. Afterremoval of hexane by evaporation, the chlorinated3-alkyl-5,5-dimethylhydantoin was obtained.

Chlorination of EDMH (Cl-EDMH). After removal of hexane, 0.4741 grams ofCl-EDMH was obtained as a while powder, yield: 50.0%. Chlorine contentdetermined by titration is 20.11% (theoretical: 18.63%).

Chlorination of BDMH (Cl-BDMH). 0.9378 grams (0.005 mol) of BDMH, 3.50grams (0.015 mol) of TCCA. After removal of hexane, 0.7890 grams ofCl-BDMH was obtained as a white powder, yield: 72.2%. Chlorine contentdetermined by titration is 18.39% (theoretical: 16.24%).

Chlorination of DMH-BH (Cl-HDMH). 0.9352 grams (0.0044 mol) of HDMH,3.10 grams (0.0132 mol) of TCCA. After removal of hexane, 0.7112 gramsof Cl-HDMH was obtained as transparent viscous liquid, yield: 65.5%.Chlorine content determined by titration is 12.83% (theoretical:14.39%).

Chlorination of DDMH (Cl-DDMH). 0.8477 grams (0.0029 mol) of DDMH, 2.00grams (0.01 mol) of TCCA. After removal of hexane, 0.92 grams of Cl-DDMHwas obtained as transparent viscous liquid, yield: 97.3%. Chlorinecontent determined by titration is 10.78% (e.g., theoretical: 10.73%).

Chlorination of ODDMH (Cl-ODDMH). 1.0058 grams (0.0026 mol) of ODDMH,2.00 grams (0.0078 mol) of TCCA. After removal of hexane, 0.9844 gramsof Cl-ODDMH was obtained as a white powder, yield: 91.2%. Chlorinecontent determined by titration is 7.93% (e.g., theoretical: 8.55%).Chlorination of DCSDMH (Cl-DCSDMH). 0.8698 grams (0.002 mol) of DCSDMH,1.40 grams (0.006 mol) of TCCA. After removal of hexane, 0.8133 grams ofCl-DCSDMH was obtained as a white powder, yield: 86.3%. Chlorine contentdetermined by titration is 7.68% (e.g., theoretical: 7.54%).

The present invention includes a self-decontaminating biocidalcomposition having the general formula 2 below.

The structure includes two heterocyclic 5-membered rings with eachhaving 2 nitrogen heteroatoms, 2 carbonyl groups and groups R¹, R² andR³, R⁴, respectively. The two heterocyclic 5-membered rings areconnected by group R⁵ attached to the nitrogen heteroatoms of each ofthe 5-membered rings. Each of the heterocyclic 5-membered rings includeseither hydrogen or a halogen as group X connected to the herteroatom ofthe 5-membered ring. R¹, R², R³, R⁴ and R⁵ may be individually be analkyl, an alkylene, an alkenyl, an alkynyl, an aryl, an alkoxy, analkylcarbonyl, an alkylcarboxyl, an amido, an amine, a halogen, ahydrogen, a carboxyl, an aromatic ring or combinations thereof. Inaddition, each of the R¹, R², R³, R⁴ and R⁵ groups may themselves beindividually modified and/or substituted with one or more an alkyl, analkylene, an alkenyl, an alkynyl, an aryl, an alkoxy, an alkylcarbonyl,an alkylcarboxyl, an amido, a carboxyl or an aromatic ring groups.

Preparation of N-halamine-containing materials. In one example, apredetermined amount of Cl-ODDMH (e.g., 1%, 2% and 4% to PU) was addedinto 5% polyurethane (Noveon) solutions in THF under-constant stirringto from a clear solution. The solution was cast onto Teflon sheets in afume hood at room temperature for 2 days to produce thin films (e.g.,170±10 μm of thickness). The films were further dried under vacuum at50° C. for 3 days. Cl-ODDMH-containing PU sheets (e.g., 4×4 cm) or discs(e.g., 0.5 cm of diameter) were cut sterilely from the films. Pure PUsheets or discs were prepared under the same conditions as controls.

In another example, a predetermined amount of Cl-ODDMH was added intoabout 5 percent PP solutions in hot o-xylene under constant stirring.After evaporation of the solvent, polymer films (e.g., thickness: about70±5 μm) were obtained by hot pressing at about 170° C. for about 15seconds. Chlorine contents of the resultant samples were determined byiodimetric titration. ODDMH-containing PP films were prepared using thesame method.

In another example, a predetermined amount of Cl-BDMH was added into 5%cellulose acetate acetone solution. The solution was coated onto wood,and cured at 60° C. for 10 minutes to form a coating.

In another example, a predetermined amount of Cl-DCSDMH was added into acommercial paint. The paint was painted onto glass slides to formpaintings. Yet in another example, a predetermined amount of HDMH wasextruded through an extruder with polyethylene, the extruded polymerswere pressed into films, and films were exposed to chlorine bleach.

Anti-biofilm functions. The samples were immersed individually in sealedtubes containing 5 mL of S. epidermidis broth suspension (10⁶′-10⁷CFU/mL of bacteria) in a shaking water bath at 37° C. and 30 RPM. After3 days of growth at 37° C. and 30 RPM (which showed substantial biofilmformation on untreated samples), the samples were taken out of thebacteria-containing tubes, washed individually with PBS (3×10 mL) toremove loosely-attached bacteria, sonicated for 20 minutes, and thenvortexed for 60 seconds. The solution was serially diluted, and 100 μLof each dilution was plated onto agar plates. The same procedure wasapplied to the untreated samples as controls. Bacterial colonies werecounted after incubation at 37° C. for between about 24 and 48 hours.SEM studies were used to confirm the biofilm controlling function. PUdiscs with or without the presence of Cl-ODDMH were immersed in 5 mL10⁶-10⁷ CFU/mL of S. epidermidis broth suspensions in a water bath at37° C. and 30 RPM. After 3 days of incubation, the discs were rinsedwith 0.1 M sodium cacodylate buffer (SCB) at pH 7.4 (e.g., 3×10 mL) toremove loosely-attached cells, and then fixed with 3% glutaraldehyde inSCB for 24 hours. After being gently washed with SCB, the samples weredehydrated through an alcohol gradient,¹⁶ dried in a critical pointdrier, mounted onto sample holders, sputter coated with gold-palladium,and observed under a SEM (e.g., Philips 515 SEM) to check for thepresence of biofilms.

Durability is an important feature of the antimicrobial functions of thesamples. After storage at about 25° C. and about 80% RH for 3 months,the biofilm-controlling functions were unchanged. Evaluation of therechargeability of the samples were preformed by first treated withabout 1.0 weight percent sodium thiosulfate solutions at roomtemperature for about 120 minutes to partially quench the chlorine, andthen re-chlorinated with about 0.6 weight percent sodium hypochloritesolutions. After about 20 cycles of the re-chlorinating treatments, thechlorine contents and antimicrobial activities of the samples wereessentially unchanged, indicating that the antimicrobial functions werefully rechargeable.

The N-halamine-containing material demonstrated anti-biofilm functions.As an example, for polyurethane samples containing 4% Cl-ODDMH, afterthree days of immersion in S. epidermidis, less than 50 CFU/cm² ofbacteria can be recovered from the samples, while for pure polyurethanesamples, under the same conditions, the recovered bacteria were higherthan 10⁵ CFU/cm². After three days, substantial biofilms were found onpure polyurethane, but no biofilm on the N-halamine-containing sampleswere observed, only limited scattered bacteria could be detected in SEMstudies.

Preparation of CADMH-containing polymeric materials. PS and HDPE wereused as the model polymers to preliminarily evaluate the antimicrobialactivities of CADMH as additives. In the preparation of CADMH-containingPS films, a certain amount of CADMH was dissolved in 5% PS solutions inTHF. The solution was poured onto glass slides. The glass slides wereput in a fume hood for 2 days at room temperature to evaporate most ofthe solvent, and then further dried in a vacuum oven at 30° C. for 3days to obtain polymer films (100±10 μm of thickness). To prepareCADMH-containing HDPE films, a predetermined amount of CADMH was addedinto 5% HDPE solutions in hot o-xylene under constant stirring. Afterevaporation of the solvent, polymer films having a thickness of about70±5 μm were obtained by hot pressing at 140° C. for 15 seconds. Thechlorine contents of the CADMH-containing PS and HDPE films weredetermined by iodimetric titration, as described above. Pure PS or HDPEfilms without the presence of CADMH were prepared using the sameprocedures as controls.

In other examples to evaluate antimicrobial activities of CADMH,Escherichia coli (e.g., E. coli, ATCC® 15597™, gram-negative) andStaphylococcus aureus subsp. aureus (e.g., S. aureus, ATCC® 6538™,gram-positive) were used as model microorganisms to challenge theantimicrobial functions of the samples. In the microbial studies, thebacteria were grown in broth solutions (e.g., LB broth for E. coli;Tryptic Soy broth for S. aureus) overnight at 37° C. Cells wereharvested in a centrifuge, washed twice with phosphate buffered saline(e.g., PBS, OmniPur®, NaCl, 8.0 g/L; KCl, 0.20 g/L; Na₂HPO₄, 1.42 g/L;KH₂PO₄, 1.36 g/L; pH 7.4), re-suspended in PBS, and then diluted toconcentrations of 108-9 CFU/mL. A known amount of CADMH (particle size:60-80 mesh) was dispersed in 10 mL of sterilized distilled water. Themixture was vortexed and then sonicated for 10 minutes. Then, 100 μL ofthe bacteria suspension were added into the CADMH-containing suspensionand the resultant mixture was vortexed for 60 seconds. After a certainperiod of contact time under constant shaking, the mixture was pouredinto 90 mL of 0.03 wt % sterilized sodium thiosulfate aqueous solutionto quench the active chlorine and stop the antimicrobial test. Ourprevious studies have shown that such a treatment does not affect thegrowth of the bacteria. The resulting solutions were vortexed for 2minutes and then serially diluted, and each dilution was placed onto LBagar (for E. coli) or Tryptic soy agar (for S. aureus). The sameprocedure was also applied to the correspondent unchlorinated samples ascontrols. Bacterial colonies on the plates were counted after incubationat 37° C. for 24 hours.

Antimicrobial activity of CADMH-containing polymers. In theantimicrobial tests of CADMH-containing PS or HDPE films, 10 μL of E.coli suspensions (e.g., 10⁸-10⁹ CFU/mL) were placed onto the surface ofa film (e.g., 4×4 cm). The film was then covered with another identicalfilm. A 100 grams weight was added onto the whole “sandwich” to ensuresufficient contact. At different contact time, the “sandwich” wastransferred into 10 mL of 0.03 wt % sodium thiosulfate aqueous solutionto quench the active chlorine of the samples. The mixture was sonicatedfor 20 minutes and vortexted for 60 seconds to remove the adherentbacteria into the solution. The resultant solution was serially diluted,and each dilution was placed onto LB agar plates. The same procedure wasalso applied to the pure PS or HDPE films as controls. Bacterialcolonies were counted after 24 hours of incubation at 37° C.

To illustrate the synthesis and characterization of the samples, FIG. 2is a scheme illustrating one method of synthesis of3-alkyl-5,5-dimethylhydantoins by the nucleophilic reaction of alkylbromide with the potassium salt of DMH, and CADMH was prepared by thechlorine exchange reaction of TCCA with the3-alkyl-5,5-dimethylhydantoins. All the reactions preceded smoothly withgood yields.

FT-IR analysis was used to characterize the reactions. As an example,FIG. 3 is an IR spectra of DMH, BD, DDMH and Cl-DDMH. In the spectrum ofDMH, the broad peak centered around 3280 cm⁻¹ is attributable to N—Hstretching vibrations, and the 1770, 1732 and 1713 cm⁻¹ bands are causedby the C═O stretching vibrations of the imide and amide groups. The C—Hstretching vibrations of BD are presented in the region of 2854cm⁻¹-2956 cm⁻¹. In the spectrum of DDMH, the C—H peaks of the alkylchain can be clearly observed. In addition, the carbonyl bands of theimide and amide groups shift to 1782 cm⁻¹ and 1707 cm⁻¹, respectively.Upon treatment with TCCA, the N—H bond in DDMH is transformed into N—Clbond. Consequently, in the spectrum of Cl-DDMH, the N—H stretchingvibration around 3280 cm⁻¹ disappears, and two new bands at 758 and 735cm⁻¹ can be detected, which are assigned to the N—Cl groups. Moreover,the transformation of N—H bonds to N—Cl groups is associated with thebreakage of N—H—-O═C hydrogen bonding in DDMH, and this results in theshifts of the C═O bands from 1782 and 1707 cm⁻¹ in DDMH to 1794 and 1728cm⁻¹ in Cl-DDMH, respectively.

The chemical structures of the samples were also characterized with ¹HNMR analysis. As a typical example, FIG. 4 shows the proton NMR spectraof BD, DMH, DDMH and Cl-DDMH. The assignments of the signals in BD are:δ=3.44 (t, H¹), 1.80 (m, H²), 1.46 (m, H³), 1.30 (m, H⁴) and 0.92 ppm(t, H⁵). In the spectrum of DMH, the methyl protons show signals at 1.64and 1.47 ppm, the imide proton shows a resonance peak at 8.14 ppm, andthe amide proton displays a single peak at 5.79 ppm. After thesubstitution reaction of DMH with BD, while the alkyl proton signals ofBD and the methyl and amide proton resonances of DMH can be clearlyobserved in the spectrum of DDMH, the imide proton signal (8.14 ppm inDMH) disappears. After chlorination, the amide proton signal can nolonger be detected in the spectrum of Cl-DDMH, indicating that the N—Hbond in DDMH is transformed into N—Cl group.

The N—H→N—Cl transformation was further confirmed by UV analysis;typical examples are presented in the UV spectrum of FIG. 5. In the UVspectra of DMH and DDMH (0.05 mol/L in methanol), the UV adsorptioncentered at 240 nm are caused by the hydantoin ring structures. Afterchlorination, DMH is transformed into 1,3-dichloro-5,5-dimethylhydantoin(DCDMH), and DDMH is transformed into Cl-DDMH. At a concentration of0.05 mol/L, a broad N-halamine peak around 280 is clearly observed inthe UV spectra of DCDMH-H and Cl-DDMH, which can be caused by thedisruption of the N—Cl bond and/or the transition from a bonding to anantibonding orbital. The presence of the 280 nm absorption is furtherconfirmed by the UV spectrum of diluted DCDMH methanol solution(DCDMH-L, 0.01 mol/L). In this spectrum, in addition to the stronghydantoin ring adsorption at 240 nm, a weak shoulder in the range of270-280 nm can be detected. The UV spectrum of diluted Cl-DDMH was alsoexamined. Unfortunately, because of the relatively low chlorine contentof Cl-DDMH (10.78% vs. 36.04% in DCDMH) and the interference of thestrong adsorption of the ring structure, the N—Cl adsorption in dilutedCl-DDMH was too weak to be detectable. Similar phenomena are alsoobserved in the UV study of other CADMH.

Thermal properties of the samples were examined with DSC, and therepresentative DSC curves are shown in FIG. 6 using DCSDMH and Cl-DCSDMHas examples. DCSDMH shows a sharp melting peak at 76.1° C. Afterchlorination, the N—H bond in DCSDMH is transformed into N—Cl group, andbecause of the lack of hydrogen bonding, the melting point of Cl-DCSDMHdecreases to 52.4° C. Moreover, an intensive exothermic peak at 176.0°C. is observed in the DSC curve of Cl-DCSDMH, which can be caused by thedecomposition of the N—Cl bond.

Antimicrobial functions. The antimicrobial activities of CADMH werechallenged with gram-negative (E. coli) and gram-positive (S. aureus)bacteria. All the samples provided potent antimicrobial functionsagainst both species. As a general observation, shorter alkyl chainlength leads to faster antimicrobial actions. For instance, as shown inthe graph of FIG. 7, at 500 ppm of active chlorine content, Cl-EDMHprovides a total kill of 10⁸-10⁹ CFU/mL of E. coli and S. aureus in lessthan 5 minutes. However, it takes Cl-HDMH 30 minutes and Cl-DCSDMH 60minutes to achieve the same antimicrobial efficacy. Antimicrobialactivities of Cl-EDMH, Cl-HDMH and Cl-DCSDMH against FIG. 7(a) E. coli(gram-negative bacteria) and FIG. 7(b) S. aureus (gram-positivebacteria). The active chlorine content in the test suspensions was 500ppm. When the active chlorine content is increased to 1000 ppm as seenin the graph of FIG. 16, the antimicrobial activities of Cl-HDMH andCl-DCSDMH are significantly improved with about 20-30 minutes for totalkill, but their bactericidal actions are still slower than that ofCl-EDMH with less than 5 minutes for total kill. Antimicrobialactivities of Cl-EDMH, Cl-HDMH and Cl-DCSDMH against FIG. 8(a) E. coli(gram-negative bacteria) and FIG. 8(b) S. aureus (gram-positivebacteria).

It has been reported that the bactericidal action of N-halamines is amanifestation of a chemical reaction involving the direct transfer ofpositive chlorines from the N-halamines to the appropriate receptors inthe cells. This chemical reaction can effectively destroy or inhibitenzymatic or metabolic cell processes, resulting in the expiration ofthe organisms. With the increase of alkyl chain length, the solubilityof the CADMH decreases. As a matter of fact, while Cl-EDMH is soluble inwater (ca. 3 g/L at 23° C.), both Cl-HDMH and Cl-DCSDMH are insoluble.The water solubility of Cl-EDMH ensures full contact of the bacteriawith Cl-EDMH molecules in the antimicrobial tests, resulting in the mostpotent antimicrobial activity with a total kill in less than 5 minutes.In the cases of Cl-HDMH and Cl-DCSDMH, however, the bacteria could onlycontact with the surfaces of the Cl-HDMH and Cl-DCSDMH particles (60-80mesh) during the microbial tests. Thus, longer contact time is neededfor a total kill of the microorganisms.

It is interesting to note that the CADMH provided faster antimicrobialaction against gram-positive bacteria than gram-negative bacteria. Forexample, at 1000 ppm of active chlorine content, after 5 minutes ofcontact, Cl-HDMH provides 2 log reduction (99% of kill) of E. coli, butit offers 7 log reduction (99.99999% of kill) of S. aureus as seen inFIG. 8. When the contact time is extended to 15 minutes, Cl-HDMHprovides 5 log reduction of E. coli (99.999% of kill), but itinactivates all the S. aureus tested (8 log reduction). This differencecan be attributed to the different structures of the bacteria. A majorstructural difference between gram-negative bacteria and gram-positivebacteria is that the cell wall of the former is overlaid with an outermembrane comprising lipopolysaccharide. This lipopolysaccharide layeroffers a supplementary barrier limiting or preventing the penetration ofantimicrobial agents into the cell. Therefore, E. coli (gram-negative)are inactivated in a longer contact period than S. aureus(gram-positive).

The CADMH showed excellent storage stability. After storage for about 4months under ambient conditions (e.g., 23±2° C., 70±5% RH), all thesamples retained more than 96% of their original chlorine contents. Theantimicrobial functions were tested monthly during the storage period,and after 4 months of storage, the minimum contact time of the samplesfor a total kill of 10⁸-10⁹ CFU/mL of E. coli or S. aureus wasunchanged.

The efficacy of CADMH as antimicrobial additives in polymeric materialswas preliminarily evaluated. PS and HDPE were used as model polymers.CADMH samples were added into PS through solvent casting, and they wereincorporated into HDPE though hot pressing. Iodimetric titration showedthat these two approaches did not affect the chlorine contents of theCADMH samples, suggesting the suitability of CADH as potential polymeradditives. While neither the original PS nor the HDPE had anyantimicrobial effects, the CADMH-containing materials provided potentantimicrobial functions. For instance, when as low as 1% of Cl-DCSDMHwas added into PS or HDPE films, the resultant films provided a totalkill of 10⁸-10⁹ CFU/mL of E. coli (the more resistant species than S.aureus) after 4 hours of contact. After storage for 4 months at 23 ±2°C. and 70±5% RH, no changes could be observed in the active chlorinecontents and the antimicrobial activities of the Cl-DCSDMH-containing PSand HDPE films. Although more studies are needed to further evaluatetheir performances, these findings point to the great potentials of theCADMH as effective antimicrobial additives for polymeric materials.

The present invention includes a self-decontaminating biocidalcomposition having the general formula 3 below.

The bicyclic ring structure (e.g., spiro rings structure sharing acommon atom) includes a heterocyclic 5-membered ring and a heterocyclic6-membered ring. The heterocyclic 5-membered ring has 2 nitrogenheteroatoms, 2 carbonyl groups and a R⁵ group connected to one of thenitrogen heteroatoms. The heterocyclic 6-membered ring has a nitrogenheteroatom and groups R¹, R², R³ and R⁴. Each of the ring structuresincludes a hydrogen or a halogen at positions X and X₁, R¹, R², R³, R⁴and R⁵ may be individually be an alkyl, an alkylene, an alkenyl, analkynyl, an aryl, an alkoxy, an alkylcarbonyl, an alkylcarboxyl, anamido, an amine, a halogen, a hydrogen, a carboxyl, an aromatic ring orcombinations thereof. In addition, each of the R¹, R², R³, R⁴ and R⁵groups may themselves individually be modified and/or substituted withone or more an alkyl, an alkylene, an alkenyl, an alkynyl, an aryl, analkoxy, an alkylcarbonyl, an alkylcarboxyl, an amido, a carboxyl or anaromatic ring groups.

The present invention includes a self-decontaminating biocidalcomposition having the general formula 4 below.

The structure includes 2 bicyclic ring structures connected by a groupR⁵ attached to the heteroatom of each of the bicyclic rings. Each of thebicyclic ring structures has a heterocyclic 5-membered ring and aheterocyclic 6-membered ring (e.g., Spiro rings structure sharing acommon atom). The heterocyclic 5-membered ring has 2 nitrogenheteroatoms and 2 carbonyl groups. The heterocyclic 5-membered ring hasa group X attached to one of the heteroatoms that may be a hydrogen or ahalogen. Similarly, the heterocyclic 6-membered ring has an X¹ groupthat may be Hydrogen or a halogen attached to the heteroatom. The 2bicyclic ring structures include groups R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸and R⁹ respectively. R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ may beindividually be an alkyl, an alkylene, an alkenyl, an alkynyl, an aryl,an alkoxy, an alkylcarbonyl, an alkylcarboxyl, an amido, an amine, ahalogen, a hydrogen, a carboxyl, an aromatic ring or combinationsthereof. In addition, each of the R¹, R², R³, R⁴, R⁵, R⁷, R⁸ and R⁹groups may themselves individually be modified and/or substituted withone or more an alkyl, an alkylene, an alkenyl, an alkynyl, an aryl, analkoxy, an alkylcarbonyl, an alkylcarboxyl, an amido, an amine, ahalogen, a hydrogen, a carboxyl or an aromatic ring groups.

Additionally, the present invention includes a self-decontaminatingbiocidal composition having the general formula 5 below.

The structure includes 2 bicyclic ring structures connected at theheteroatoms through group R¹⁰. Each of the bicyclic ring structures hasa heterocyclic 5-membered ring and a heterocyclic 6-membered ring (e.g.,spiro rings structure sharing a common atom). The heterocyclic5-membered ring has 2 nitrogen heteroatoms, 2 carbonyl groups and groupsR⁵ and R¹¹ respectively. The heterocyclic 5-membered ring also has groupX that may be a hydrogen or a halogen attached to one of theheteroatoms. The heterocyclic 6-membered ring has a nitrogen heteroatomand groups R¹, R², R³, R⁴ and R⁶, R⁷, R⁸, R⁹ respectively. Groups R¹,R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R⁹ and R¹¹ may be individually be analkyl, an alkylene, an alkenyl, an alkynyl, an aryl, an alkoxy, analkylcarbonyl, an alkylcarboxyl, an amido, a carboxyl, an aromatic ringor combinations thereof. In addition, each of the R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, R⁹ and R¹¹ groups may themselves individually bemodified and/or substituted with one or more an alkyl, an alkylene, analkenyl, an alkynyl, an aryl, an alkoxy, an alkylcarbonyl, analkylcarboxyl, an amido, an amine, a halogen, a hydrogen, a carboxyl oran aromatic ring groups.

In other examples to show the synthesis of N-halamine-based chemicalwith general formula 3 as shown in FIG. 1, 1-bromohexane (BH),1-bromododecane (BD), 1-bromooctadecane (BOD) and7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (TMTDD) areavailable from ALDRICH. Before use, the BH, BD and BOD were distilled at80° C. and reduced pressure to remove impurities; TMTDD powder weredissolved in dilute sodium hydroxide solution and re-precipitated by theaddition of hydrochloric acid, after filtering, the received whitesamples were thoroughly washed with distilled water.

To a one-neck-round-bottom flask was added a mixture of 30 mL ofabsolute ethanol, 5.63 grams (0.025 mol) of TMTDD, and 1.68 grams (0.03mol) of potassium hydroxide. The mixture was heated to form a clearsolution. Then the solid potassium salt of the TMTDD was isolated byevaporation of the ethanol solvent and the water produced in thereaction under reduced pressure. This slat was dried under vacuum at 60°C. for three days to form the anhydrous potassium salt. The dry salt wasthen placed back in the flask fit with condenser where it was mixed with150 mL of anhydrous N,N-dimethylformamide (DMF), and 0.025 mol of1-brominated hydrocarbon. The mixture was then heated at 95° C., keepingconstant stirring, for 4 hours. After completion of the reaction, thereaction mixture was cooled, and the solid was removed by filtration.The DMF solvent was removed by distillation and the residual substancewas recrystallized from absolute ethanol.

7,7,9,9-tetramethyl-3-hexyl-1,3,8-triazaspiro[4,5]decane-2,4-dione(TMTDD-BH) 4.13 grams of BH. After recrystallization, 6.82 grams of7,7,9,9-tetramethyl-3-hexyl-1,3,8-triazaspiro[4.5]decane-2,4-dione(TMTDD-H, white crystals) was obtained, indicating 88.2% yield.7,7,9,9-tetramethyl-3-octadecyl-1,3,8-triazaspiro[4,5]decane-2,4-dione(TMTDD-BD) 6.23 grams of BD. After recrystallization, 8.24 grams of7,7,9,9-tetramethyl-3-dodecyl-1,3,8-triazaspiro[4.5]decane-2,4-dione(TMTDD-D, white crystals) was obtained, indicating 83.7% yield.7,7,9,9-tetramethyl-3-stearyl-1,3,8-triazaspiro[4,5]decane-2,4-dione(TMTDD-BOD) 8.34 grams of BOD. After recrystallization, 11.09 grams of7,7,9,9-tetramethyl-3-octadecyl-1,3,8-triazaspiro[4.5]decane-2,4-dione(TMTDD-OD, white crystals) was obtained, indicating 92.9% yield.

The present invention includes a self-decontaminating monomeric orpolymeric biocidal composition having the general formula 6 below.

The structure includes a heterocyclic 6-membered ring having 3 nitrogenheteroatoms and 2 amine groups having X¹, X² and X³, X⁴, respectively.The heterocyclic 6-membered ring also includes group R that may be usedto connect the heterocyclic 6-membered ring to a surface, a compound ora polymer. The X¹, X², X³, X⁴ and R groups may independently behydrogen, a halogen, an alkyl, an alkylene, an alkenyl, an alkynyl, anaryl, an alkoxy, an alkylcarbonyl, an alkylcarboxyl, an amido, acarboxyl, an aromatic ring or combinations thereof. In addition, each ofthe X¹, X², X³, X⁴ and R groups may themselves be individually modifiedand/or substituted with one or more an alkyl, an alkylene, an alkenyl,an alkynyl, an aryl, an alkoxy, an alkylcarbonyl, an alkylcarboxyl, anamido, a carboxyl, amine, halogen, hydrogen or an aromatic ring groups.

The present invention includes a self-decontaminating monomeric orpolymeric biocidal composition having the general formula 7 below.

The composition includes an aliphatic chain attached to a heterocyclicring. The aliphatic chain may contain a first aliphatic chain havingbetween 1 and 40 repeats (m=1 to 40) connected to a second halogenatedaliphatic chain having between 0 and 40 repeats (n=0 to 40).Alternatively, the first aliphatic chain may be halogenated or both thefirst aliphatic chain and the second aliphatic chain may be halogenated.Although the aliphatic chains are depicted as ethyl groups, the numberof carbons, the number of bonds and the branching may vary depending onthe particular application, e.g., the aliphatic chains may independentlybe a methyl, an ethyl, a propyl, an isopropyl, a Butyl, an isobutyl, asec-Butyl, a tert-Butyl group and so forth. In addition, the aliphaticchains may be substituted or modified by a hydrogen, a halogen, analkyl, an alkylene, an alkenyl, an alkynyl, an aryl, an alkoxy, analkylcarbonyl, an alkylcarboxyl, an amido, a carboxyl, an aromatic ringor combinations thereof. The heterocyclic ring is a 5-membered ring with2 nitrogen heteroatoms, 2 carbonyl groups and groups R¹ and R². groupsR¹ and R² may be be individually an alkyl, an alkylene, an alkenyl, analkynyl, an aryl, an alkoxy, an alkylcarbonyl, an alkylcarboxyl, anamido, an amine, a halogen, a hydrogen, a carboxyl, an aromatic ring orcombinations thereof. In addition, each of the R¹ and R² groups maythemselves be individually modified and/or substituted with one or morean alkyl, an alkylene, an alkenyl, an alkynyl, an aryl, an alkoxy, analkylcarbonyl, an alkylcarboxyl, an amido, a carboxyl or an aromaticring groups.

The present invention includes a self-decontaminating monomeric orpolymeric biocidal composition having the general formula 8 below.

The composition includes an aliphatic chain attached to a bicyclic ringstructure. The aliphatic chain may contain a first aliphatic chainhaving between 1 and 40 repeats (m=1 to 40) connected to a secondhalogenated aliphatic chain having between 0 and 40 repeats (n=0 to 40).Alternatively, the first aliphatic chain may be halogenated or both thefirst aliphatic chain and the second aliphatic chain may be halogenated.Although the aliphatic chains are depicted as ethyl groups, the numberof carbons and the branching may vary depending on the particularapplication, e.g., the aliphatic chains may independently be a methyl,an ethyl, a propyl, an isopropyl, a Butyl, an isobutyl, a sec-Butyl, atert-Butyl group and so forth. In addition, the aliphatic chains may besubstituted or modified by a hydrogen, a halogen, an alkyl, an alkylene,an alkenyl, an alkynyl, an aryl, an alkoxy, an alkylcarbonyl, analkylcarboxyl, an amido, a carboxyl, an aromatic ring or combinationsthereof. The bicyclic ring structure (e.g., spiro rings structuresharing a common atom) includes a heterocyclic 5-membered ring and aheterocyclic 6-membered ring. The heterocyclic 5-membered ring has 2nitrogen heteroatoms, 2 carbonyl groups. The heterocyclic 5-memberedring is attached to the aliphatic chain at one of the heteroatoms andincludes group X at the other heteroatom that may be a hydrogen or ahalogen. The heterocyclic 6-membered ring has a nitrogen heteroatom andgroups R¹, R², R³ and R⁴. The nitrogen heteroatom is attached to group Xthat may be a hydrogen or a halogen at position. R¹, R², R³, R⁴ and R⁵may be individually be an alkyl, an alkylene, an alkenyl, an alkynyl, anaryl, an alkoxy, an alkylcarbonyl, an alkylcarboxyl, an amido, an amine,a halogen, a hydrogen, a carboxyl, an aromatic ring or combinationsthereof. In addition, each of the groups may themselves individually bemodified and/or substituted with one or more an alkyl, an alkylene, analkenyl, an alkynyl, an aryl, an alkoxy, an alkylcarbonyl, analkylcarboxyl, an amido, a carboxyl or an aromatic ring groups.

The structure may be substituted and/or modified. Although the specificexamples list here contain heterocyclic 5 and 6-membered rings, thenumber of members to the rings, the type of heteroatoms, the location ofthe heteroatoms, the number of rings, the connection between rings, andso forth may be varied by the skilled artisan.

The present invention also provides a method of using piperidine-basedN-halo-hinder amines as biofilm-controlling and photo and thermalstabilization agents. In a previous patent application by the sameinventors (Sun, Y.; Chen, Z. U.S. Patent application, No. 60/640,985,pending and incorporated herein by reference), piperidine-basedN-halo-hinder amines were used as antimicrobial agents.

In one example, a hindered amine light stabilizer, (e.g.,bis(2,2,6,6-tetramethyl-4-piperidyl)sebacate (BTMP)) was purchased fromAldrich and recrystallized from petroleum ether. Isotactic polypropylene(e.g, PP, Aldrich) was purified by dissolution in hot o-xylene followedby precipitation with methanol.

Preparation of bis(N-chloro-2,2,6,6-tetramethyl-4-piperidinyl)sebacate(Cl-BTMP). BTMP was submerged in about 0.6 weight percent sodiumhypochlorite aqueous solutions containing about 0.05 weight percent ofTriton X-100 at room temperature for 4 hours under constant stirring.The bath ratios were kept at about 1:30 and the pH values were adjustedto about 7.0 using pH buffers. After chlorination, the powders werecollected, washed thoroughly with a large amount of distilled water,filtered and dried at ambient temperature under reduced pressure. Afterrecrystallization from petroleum ether, Cl-BTMP was obtained ascolorless needles.

The structures of the N-halo hindered amines were characterized. Asexamples, FIG. 9 shows the ¹H NMR spectra of the samples to confirm thechemical structure of Cl-BTMP. In the spectrum of BTMP, the aminoprotons showed a weak and broad peak at 0.71 ppm.¹⁶⁻¹⁸ After bleachtreatment, the N—H group was transformed into N—Cl structure, and the0.71 ppm signal disappeared in the spectrum of Cl-BTMP.

FIG. 10 shows the ¹³C NMR spectra of the samples to confirm the chemicalstructure of Cl-BTMP. Prior to chlorination, the two neighboring carbons(Ca) of the N—H group in BTMP showed a peak at 51.4 ppm, which shiftedto 62.6 ppm upon bleach treatment (Ca′).

FIG. 11 is a UV/VIS spectrum of Cl-BTMP. At higher than 250 nm, BTMP didnot show any absorption. However, after chlorination, a broad peakcentered at 279 nm could be detected in the spectrum of Cl-BTMP.

The piperidine-based N-halo-hinder amines also show photo and thermalstabilizing effects in polymers, such as polypropylene. In one example,a predetermined amount of Cl-BTMP was added into about 5 percent PPsolutions in hot o-xylene under constant stirring. After evaporation ofthe solvent, polymer films (e.g., thickness: about 70±5 μm) wereobtained by hot pressing at about 170° C. for about 15 seconds. Chlorinecontents of the resultant samples were determined by iodimetrictitration. BTMP-containing PP films were prepared using the same method.

The photo stability was characterized following ASTM D 4329 Cycle A(e.g., about 8 hour UV treatment with uninsulated black panel at about60±3° C.; about 4 hour condensation with uninsulated black panel atabout 50±3° C.) using a QUA accelerated weathering tester (Q-panelproducts Inc., Cleveland, Ohio). The thermal stability of the sampleswas determined by oven aging at about 130° C. In the photo and thermalstability studies, the carbonyl index of the samples was used as ameasure to evaluate the stabilizing effects of BTMP or Cl-BTMP followingestablished methods. In the photo or thermal treatments, the FT-IRspectra of the samples were collected at different periods of time andthe carbonyl index at 1713 cm⁻¹ was calculated according to thefollowing equation:Carbonyl index=[(logI ₀ /I _(t))/d]×100where I₀ is the intensity of incident light, It is the intensity oftransmitted light, and d is film thickness (μm). Because the formationof carbonyl groups (e.g., ketones, carboxylic acids, and esters) isrelated to PP degradation, higher carbonyl index values indicate lowerstabilizing effects.¹⁴

FIGS. 12A and 12B are graphs of the carbonyl index of the film samplesin photo and thermal stability studies.^(14c) FIG. 12A is a graph of theUV treatments showing the carbonyl index of pure PP increased rapidly,implying fast oxidization of the samples. In the presence of BTMP orCl-BTMP, the carbonyl index of the sample was essentially unchanged upto about 600 hours of UV irradiation. Similar results were obtained inthe thermal stability studies, as shown in FIG. 12B.

FIGS. 13A, 13B and 13C are FT-IR spectra of the samples after differentperiods of UV irradiation where the 1735 cm⁻¹ peak was caused by thecarbonyl group of BTMP or Cl-BTMP. All FT-IR spectra were normalized tothe CH₃ symmetric bend peak at 1377 cm⁻¹.^(1,2) FIG. 13A is a FT-IRspectra of the pure PP films, while FIGS. 13B and 13C are FT-IR spectraof PP films containing about 0.5 weight percent of BTMP and Cl-BTMPrespectively.

FIGS. 14A, 14B and 14C are FT-IR spectra of the samples after differentperiods of thermal aging at 130° C. where the 1735 cm⁻¹ peak was causedby the carbonyl group of BTMP or Cl-BTMP. All FT-IR spectra werenormalized to the CH₃ symmetric bend peak at 1377 cm⁻¹.^(27,28) FIG. 14Ais a FT-IR spectra of the pure PP films, while FIGS. 14B and 14C areFT-IR spectra of PP films containing about 0.5 weight percent of BTMPand Cl-BTMP respectively. FIGS. 15A, 15B and 15C are FT-IR spectra ofthe samples after different periods of thermal aging. FIG. 15A is aFT-IR spectra of the pure PP films, while FIGS. 15B and 15C are FT-IRspectra of PP films containing about 0.5 weight percent of BTMP andCl-BTMP respectively.

Dfs FIG. 16 is a graph of the chlorine content of Cl-BTMP afterdifferent cycles of re-chlorination treatments. FIG. 17 illustratesexemplar N-halamine compounds that may be used with the presentinvention. FIG. 17 indicates an aliphatic chain attached to a bicyclicring structure. The aliphatic chain may contain between 1 and 40 repeats(n=1 to 40) with 4, 10 and 16 carbons given as an example. Although thealiphatic chain is depicted as linear group, the number of carbons andthe branching may vary depending on the particular application. Inaddition, the aliphatic chain may be substituted or modified by ahydrogen, a halogen, an alkyl, an alkylene, an alkenyl, an alkynyl, anaryl, an alkoxy, an alkylcarbonyl, an alkylcarboxyl, an amido, acarboxyl, an aromatic ring or combinations thereof. The bicyclic ringstructure (e.g., spiro rings structure sharing a common atom) includes aheterocyclic 5-membered ring and a heterocyclic 6-membered ring. Theheterocyclic 5-membered ring has 2 nitrogen heteroatoms, 2 carbonylgroups. The heterocyclic 5-membered ring is attached to the aliphaticchain at one of the heteroatoms and includes group X at the otherheteroatom that may be a hydrogen (or a halogen not shown). Theheterocyclic 6-membered ring has a nitrogen heteroatom attached ahydrogen (or a halogen not shown).

The monomeric and polymeric N-halamine compounds of the presentinvention for anti-biofilm and photo and thermal stabilizingapplications are compounds including sterically hindered N-halo-aminewith a molecular weight higher than 200 g/mol, having the moiety of2,2,6,6-tetramethyl-N-halo-4-piperidinyl structure, For example, in someembodiments the sterically hindered N-halo-amine isBis(N—X-2,2,6,6-tetramethyl-4-piperidyl)sebacate;Poly[[6-[(1,1,3,3-tetramethylbutyl)amino]-s-triazine-2,4-diyl]-N—X-[(2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene-[(2,2,6,6-tetramethyl-4-piperidylimino]];N—X-[(4-piperidyl)alkyl formate];Poly[(6-morpholino-s-triazine-2,4-diyl)-N—X-[2,2,6,6-tetramethyl-4-piperidyl]imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]];3-Dodecyl-N-chloro-(2,2,6,6-tetramethyl-4-piperidinyl)succinimide;2,2,4,4-Tetramethyl-N—X-7-oxa-3,20-diazadispiro[5.1.11.2]-heneicosan-21-one;D-Glucitol,1,3:2,4-bis-O-(N-chloro-2,2,6,6-tetramethyl-4-piperidinylidene);1,1′-ethylenebis(N—X-3,3,5,5-tetramethyl-piperazinone);N—X-2,2,4,4-tetramethyl-7-oxa-20-(oxiranylmethyl)-3,20-diazadispiro[5.1.11.2]henicosan-21-one;1,2,3,4-Butanetetracarboxylic acid, polymer withβ,β,β′,β′-tetramethyl-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diethanol,N—X-2,2,6,6-tetramethyl-4-piperidinyl ester;Poly[oxy[methyl[3-[N—X—(2,2,6,6-tetramethyl-4-piperidinyl)-oxy]propyl]silylene]];1,1′,1″-[1,3,5-Triazine-2,4-6-triyltris[(cyclohexylimino)ethylene]]tris(N-chloro-3,3,5,5-tetramethyl-piperazinone);and mixtures and combinations thereof; wherein X is Cl or Br.

The present invention may be used as an additive to different materials.The present invention relates to monomeric and polymeric N-halaminehaving ring structures wherein 3 members of the ring are carbon, one ormore members of the ring is a nitrogen or oxygen heteroatom. Thecompound also includes one or more chlorine, bromine or hydrogen atoms,hydroxyl, C₁-C₄₀ alkyl, benzyl, substituted benzyl, phenyl andsubstituted phenyl; R¹ to R¹⁰ are each independently selected from thegroup consisting of hydrogen, C₁-C₄₀ alkyl, benzyl, substituted benzyl,phenyl and substituted phenyl. A method of using the present inventionfor producing a biocidal material or paint/coating through halogenationwith chlorine or bromine is also disclosed. The biocidal material can beused directly, or applied as a coating or film or paint onto a pluralityof substrates useful for antimicrobial and anti-biofilm properties. Thebiocidal properties can be regenerated by renewed halogenation inchlorine- or bromine-containing solutions. In addition tobiofilm-controlling effect, the piperidine-based N-halo-hindered aminescan also provide photo and thermal protective functions.

The novel N-halamine biocidal compounds described herein containheterocyclic units, which have stable N—Cl or N—Br chemical bondsnecessary for biocidal action. The heterocyclic N-halamine units cancomprise from 4 to 7-membered rings and preferably 5 to 6-memberedrings, wherein nitrogen is a heteroatom and oxygen can be a heteroatom,and which can have one or two carbonyl groups. The balance of the ringsis carbon. The rings can have from three to six carbon members, from oneto three nitrogen heteroatoms and 0 to 1 oxygen heteroatom. A carbonatom of these heterocyclic moieties can be joined by a linkage to anadditional heterocyclic N-halamine unit by one of many possible linkageswhich attach to each N-halamine unit at a single non-carbonyl carbonatom, such as a lower alkyl, i.e., a three to eleven carbon chain thatcan be branched when greater than three carbons, or a phenyl-loweralkyl-phenyl, i.e., two phenyl groups joined by a three to 30 carbonchain that can be branched when greater than three carbons wherein onephenyl attaches to a cyclic N-halamine unit and the other phenylattaches to a neighboring cyclic N-halamine unit. Additionally, theN-halamine units can comprise a 5- or 6-membered ring having twonitrogen heteroatoms and three (for the 5-membered ring) to four (forthe 6-membered ring) carbon members, one of which can be a carbonylgroup, and attaching to neighboring N-halamine units in the polymer viamethylene linkages which attach to each N-halamine unit at two of thenon-carbonyl carbon ring members.

In addition, the present invention provides the introduction of organicN-halamine structures into polymeric materials to provide antimicrobialfunctions by covalently binding N-halamine precursors (e.g., hydantoins)onto a target polymer. After halogenation, N-halalmine structures areformed in situ, and the resultant polymers provide potent antimicrobialfunctions against a broad range of microorganisms.

Various materials be treated using the methods of the present invention.Polymers suitable for use in the present invention include, but are notlimited to, a plastic, a rubber, a textile material, a paint, a surfacecoating, an adhesives, cellulose, a polyester, wood pulp, paper, anabsorbent, and a polyester/cellulose blend, inorganic substances such asglass, metallic and ceramic.

The polymeric plastics suitable for the present invention includethermoplastic or thermosetting resins. The thermoplastics include, butare not limited to, polyethylene, polypropylene, polystyrene andpolyvinylchloride. Thermoplastics also include, polyamideimide,polyethersulfone, polyarylsulfone, polyetherimide, polyarylate,polysulfone, polycarbonate and polystyrene. Additional thermoplasticsinclude, but are not limited to, polyetherketone, polyetheretherketone,polytetrafluoroethylene, nylon-6,6, nylon-6,12, nylon-11, nylon-12,acetal resin, polypropylene, and high and low density polyethylene.

The present invention will prevent the growth and biofilm-formation ofundesirable organisms, such as the bacteria genera Staphylococcus,Pseudomonas, Salmonella, Shigella, Legionella, Methylobacterium,Klebsiella, and Bacillus; the fungi genera Candida, Rhodoturula, andmolds such as mildew; the protozoa genera Giardia, Entamoeba, andCryptosporidium; the viruses poliovirus, rotavirus, HIV, andherpesvirus; and the algae genera Anabaena, Oscillatoria, and Chlorella;and other sources of biofouling on surfaces. In these applications, thecontents of the N-halamine compounds are in the range of between about0.1% and about 20%.

The present invention includes a method of forming N-halamine-containingmaterials, which includes synthesizing the N-halamines, and adding theN-halamines to the target materials by solution blending, mechanicalmixing, coating, painting, laminating and/or thermal mixing. Themixtures can be used directly or can be processed into desired articles.The present invention also includes adding precursors of the N-halaminesto the target materials by solution mixing, mechanical blending,coating, painting, laminating and/or thermal mixing. The mixtures or thearticles processed from the mixtures are then treated with halogensources (e.g., chlorine bleach) to provide the antimicrobial,anti-biofilm, and/or photo and thermal stabilizing functions.

The desired functions can be lost caused by extensive uses and/orprolonged storage, in which the N-halamine structures change back to theprecursors; however, because the compounds are not lost, the functionscan be easily recharged by a simple exposure to halogen sources (e.g.,bleach solutions).

The present invention provides a practical, flexible and cost-effectiveapplication to transform a wide range of materials into durable andrechargeable biocidal and biofilm-controlling materials, which will findwide applications in medical devices, hospital equipment, waterpurification/delivery systems, food storage and food packaging, hygienicproducts, bio-protective applications, and other related challengingenvironment where self-decontamination of the material is needed. Inaddition to biofilm-controlling, the piperidine-based N-halo-hinderedamines can also provide photo and thermal stabilizing functions.

The present invention includes N-halamine biocidal composition havingthe formula 1, 2, 3, 4, 5, 6, 7, 8 and combinations thereof, wherein X,X¹, X², X³ and X⁴ are individually a Hydrogen or a halogen; R¹ to R¹⁰are independently hydrogens, halogens, one or more C₁ to C₄₀ alkyl, C₁to C₄₀ alkylene, C₁ to C₄₀ alkenyl, C₁ to C₄₀ alkynyl, C₁ to C₄₀ aryl,C₁ to C₄₀ alkoxy, C₁ to C₄₀ alkylcarbonyl, C₁ to C₄₀ alkylcarboxyl, C₁to C₄₀ amido, C₁ to C₄₀ carboxyl, or combinations thereof.

For example, the present invention provides a rechargeable N-halaminebiocidal compound including3-substituted-1-N-halo-5,5-disubstituted-hydantoin;3,3′-bissubstituted-1,1′-N-halo-5,5,5′5′-substituted-2,2′,4,4′-imidazolidinedione;1,3,8-Triaza-3-substituted-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decane;3,3′-disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,8,8′N-halo-2,4-dione;8,8′-disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,3,3′N-halo-2,4-dione;Vinyl chloride-co-3-vinyl-N-halo-5,5-disubstituted hydantoin; Vinylchloride-co-3-vinyl-1,3,8-Triaza-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decane.

The present invention also includes piperidine-based N-halo-hinderedamines with a molecular weight higher than 200 g/mol, comprising themoiety of 2,2,6,6-tetramethyl-N-halo-4-piperidinyl structure, thesterically hindered N-halo-amine is selected from:

-   Bis(N—X-2,2,6,6-tetramethyl-4-piperidyl)sebacate;-   Poly[[6-[(1,1,3,3-tetramethylbutyl)amino]-s-triazine-2,4-diyl]-N—X-[(2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene-[(2,2,6,6-tetramethyl-4-piperidylimino]];-   N—X-[(4-piperidyl)alkyl formate];-   Poly[(6-morpholino-s-triazine-2,4-diyl)-N—X-[2,2,6,6-tetramethyl-4-piperidyl]imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]];-   3-Dodecyl-N-chloro-(2,2,6,6-tetramethyl-4-piperidinyl)succinimide;-   2,2,4,4-Tetramethyl-N—X-7-oxa-3,20-diazadispiro[5.1.11.2]-heneicosan-21-one;-   D-Glucitol,    1,3:2,4-bis-O-(N-chloro-2,2,6,6-tetramethyl-4-piperidinylidene);-   1,1′-ethylenebis(N—X-3,3,5,5-tetramethyl-piperazinone);-   N—X-2,2,4,4-tetramethyl-7-oxa-20-(oxiranylmethyl)-3,20-diazadispiro[5.1.11.2]henicosan-21-one;-   1,2,3,4-Butanetetracarboxylic acid, polymer with    β,β,β′,β′-tetramethyl-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diethanol,    N—X-2,2,6,6-tetramethyl-4-piperidinyl ester;-   Poly[oxy[methyl[3-[N—X—(2,2,6,6-tetramethyl-4-piperidinyl)-oxy]propyl]silylene]];-   1,1′,1″-[1,3,5-Triazine-2,4-6-triyltris[(cyclohexylimino)ethylene]]tris(N-chloro-3,3,5,5-tetramethyl-piperazinone);    and mixtures and combinations thereof, wherein X is Cl or Br. The    piperidine-based N-halo-hindered amines provide biofilm-controlling    functions as well as photo and thermal stabilizing functions.

The present invention includes a biofilm-controlling and photo andthermal stabilizing additive having a sterically hindered N-halo-aminewith a molecular weight higher than 200 g/mol. In one example, thesterically hindered N-halo-amine is a2,2,6,6-tetramethyl-N-chloro-4-piperidinyl. In another example thesterically hindered N-halo-amine isBis(N—X-2,2,6,6-tetramethyl-4-piperidyl sebacate;Poly[[6-[(1,1,3,3-tetramethylbutyl)amino]-s-triazine-2,4-diyl]-N—X-[(2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene-[(2,2,6,6-tetramethyl-4-piperidylimino]];N—X-[(4-piperidyl)alkyl formate];Poly[(6-morpholino-s-triazine-2,4-diyl)-N—X-[2,2,6,6-tetramethyl-4-piperidyl]imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]];3-Dodecyl-N-chloro-(2,2,6,6-tetramethyl-4-piperidinyl)succinimide;2,2,4,4-Tetramethyl-N—X-7-oxa-3,20-diazadispiro[5.1.11.2]-heneicosan-21-one;D-Glucitol,1,3:2,4-bis-O-(N-chloro-2,2,6,6-tetramethyl-4-piperidinylidene);1,1′-ethylenebis(N—X-3,3,5,5-tetramethyl-piperazinone);N—X-2,2,4,4-tetramethyl-7-oxa-20-(oxiranylmethyl)-3,20-diazadispiro[5.1.11.2]henicosan-21-one;1,2,3,4-Butanetetracarboxylic acid, polymer withβ,β,β′,β′-tetramethyl-2,4,8,10-tetraoxaspiro[5.5])undecane-3,9-diethanol,N—X-2,2,6,6-tetramethyl-4-piperidinyl ester;Poly[oxy[methyl[3-[N—X—(2,2,6,6-tetramethyl-4-piperidinyl)-oxy]propyl]silylene]];1,1′,1″-[1,3,5-Triazine-2,4-6-triyltris[(cyclohexylimino)ethylene]]tris(N-chloro-3,3,5,5-tetramethyl-piperazinone);and mixtures and combinations thereof, wherein X is Cl, Br or acombination thereof.

The present invention may be made mixed with a material prior, during orafter material or article formation and provide anti-biofilm, thermaland photo stabilizing function. The material of the present inventioncan be subjected to extrusion, injection molding, hot pressing, coating,painting, laminating, and solvent casting, mixtures and combinationsthereof and formed into a bead, a film, a tube, a sheet, a thread, asuture, a gauze, a bandage, an adhesive bandage, a vessel, a container,a cistern, a filter, a membrane, a coating, a paint and combinationsthereof.

Another example of the present invention includes a hinderedN-halo-amine including Bis(N—X-2,2,6,6-tetramethyl-4-piperidyl)sebacate;Poly[[6-[(1,1,3,3-tetramethylbutyl)amino]-s-triazine-2,4-diyl]-N—X-[(2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene-[(2,2,6,6-tetramethyl-4-piperidylimino]];N—X-[(4-piperidyl)alkyl formate];Poly[(6-morpholino-s-triazine-2,4-diyl)-N—X-[2,2,6,6-tetramethyl-4-piperidyl]imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]];3-Dodecyl-N-chloro-(2,2,6,6-tetramethyl-4-piperidinyl)succinimide;2,2,4,4-Tetramethyl-N—X-7-oxa-3,20-diazadispiro[5.1.11.2]-heneicosan-21-one;D-Glucitol,1,3:2,4-bis-O-(N-chloro-2,2,6,6-tetramethyl-4-piperidinylidene);1,1′-ethylenebis(N—X-3,3,5,5-tetramethyl-piperazinone);N—X-2,2,4,4-tetramethyl-7-oxa-20-(oxiranylmethyl)-3,20-diazadispiro[5.1.11.2]henicosan-21-one;1,2,3,4-Butanetetracarboxylic acid, polymer withβ,β,β′,β′-tetramethyl-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diethanol,N—X-2,2,6,6-tetramethyl-4-piperidinyl ester;Poly[oxy[methyl[3-[N—X—(2,2,6,6-tetramethyl-4-piperidinyl)-oxy]propyl]silylene]];1,1′,1″-[1,3,5-Triazine-2,4-6-triyltris[(cyclohexylimino)ethylene]]tris(N-chloro-3,3,5,5-tetramethyl-piperazinone);and mixtures and combinations thereof, wherein X is Cl, Br orcombinations thereof.

The present invention includes a method of making a biofilm controllingmaterial which is photo and thermal treatment stable by forming aN-halamine biocidal compound which is added to one or more halogensources, wherein the N-halamine biocidal compound is transformed intoone or more active N-halamine biocidal compounds. Biofilm controllingmaterial which are stable to photo and thermal treatment may be made bymixing a sterically hindered amine light stabilizer with a source ofhalide atoms to form a sterically hindered N-halo-amine and forming amaterial in the presence of the sterically hindered N-halo-amine.

The present invention also includes a method of recharging abiofilm-controlling material, which are stable to photo and thermalchallenge by exposing a sterically hindered amine stabilizer to a sourceof halide atoms.

In the claims, all transitional phrases such as “comprising,”“including,” “carrying,” “having,” “containing,” “involving,” and thelike are to be understood to be open-ended, i.e., to mean including butnot limited to. Only the transitional phrases “consisting of” and“consisting essentially of,” respectively, shall be closed orsemi-closed transitional phrases.

It will be understood that particular embodiments described herein areshown by way of illustration and not as limitations of the invention.The principal features of this invention can be employed in variousembodiments without departing from the scope of the invention. Thoseskilled in the art will recognize, or be able to ascertain using no morethan routine experimentation, numerous equivalents to the specificprocedures described herein. Such equivalents are considered to bewithin the scope of this invention and are covered by the claims.

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations can be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. All such similar substitutes andmodifications apparent to those skilled in the art are deemed to bewithin the spirit, scope and concept of the invention as defined by theappended claims

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1. A biofilm-controlling and biocidal N-halamine composition comprising:one or more 3 to 10 membered rings comprising one or more nitrogenheteroatoms, wherein one or more halogen associate with the one or morenitrogen heteroatoms and control biofilm growth.
 2. The composition ofclaim 1, wherein the a N-halamine biocidal composition comprises formula1, 2, 3, 4, 5, 6, 7, 8 or combinations thereof:

wherein X, X¹, X², X³ and X⁴ are individually a hydrogen, a halogen, analkyl, an alkylene, an amino, an alkynyl, an alkoxy; R¹ to R¹⁰ areindependently hydrogens, halogens, one or more C₁ to C₄₀ alkyl, C₁ toC₄₀ alkylene, C₁ to C₄₀ alkenyl, C₁ to C₄₀ alkynyl, C₁ to C₄₀ aryl, C₁to C₄₀ alkoxy, C₁ to C₄₀ alkylcarbonyl, C₁ to C₄₀ alkylcarboxyl, C¹ toC₄₀ amido, C₁ to C₄₀ carboxyl, or combinations thereof.
 3. Thecomposition of claim 1, wherein the N-halamine biocidal composition ismixed with a second material to produce an article.
 4. The compositionof claim 1, wherein the N-halamine biocidal composition is integratedinto a bead, a film, a tube, a sheet, a thread, a suture, a gauze, abandage, an adhesive bandage, a vessel, a container, a cistern, afilter, a membrane, a coating, a paint, a solution, a polymer andcombinations thereof.
 5. A method of making a rechargeable antimicrobialanti-biofilm article comprising the steps of: adding one or moreN-halamine biocidal compounds comprising one or more 3 to 10 memberedrings and one or more nitrogen heteroatoms to a target material to beused directly or processed into a rechargeable antimicrobialanti-biofilm article.
 6. The method of claim 5, wherein the one or moreN-halamine biocidal compounds are added by solution blending, mechanicalmixing, painting, coating, laminating, thermal mixing and combinationsthereof.
 7. The method of claim 5, wherein the one or more N-halaminebiocidal compounds comprises3-substituted-1-N-halo-5,5-disubstituted-hydantoin;3,3′-bissubstituted-1,1′-N-halo-5,5,5′5′-substituted-2,2′,4,4′-imidazolidinedione;1,3,8-Triaza-3-substituted-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decane;3,3′-disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,8,8′N-halo-2,4-dione;8,8′-disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,3,3′N-halo-2,4-dione;Vinyl chloride-co-3-vinyl-N-halo-5,5-disubstituted hydantoin; Vinylchloride-co-3-vinyl-1,3,8-Triaza-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decane,1,3-bis(hydroxylmethyl)-5,5-dimethylhydantoin,1-chloro-3-ethyl-5,5-dimethylhydantoins,1-chloro-3-dodecyl-5,5-dimethylhydantoin,1-chloro-3-octadecyl-5,5-dimethylhydantoin,1-chloro-3-docosyl-5,5-dimethylhydantoin,7,7,9,9-tetramethyl-3-hexyl-1,3,8-triazaspiro[4,5]decane-2,4-dione,7,7,9,9-tetramethyl-3-octadecyl-1,3,8-triazaspiro[4,5]decane-2,4-dione,7,7,9,9-tetramethyl-3-dodecyl-1,3,8-triazaspiro[4.5]decane-2,4-dione,7,7,9,9-tetramethyl-3-stearyl-1,3,8-triazaspiro[4,5]decane-2,4-dione,7,7,9,9-tetramethyl-3-octadecyl-1,3,8-triazaspiro[4.5]decane-2,4-dioneand mixtures thereof.
 8. The method of claim 5, wherein the one or moreN-halamine biocidal compounds further comprise one or more alkyl groups,alkylene groups, alkenyl groups, alkynyl groups, aryl groups, alkoxygroups, alkylcarbonyl groups, alkylcarboxyl groups, amido groups,carboxyl groups, halogens, hydrogens or combinations thereof.
 9. Themethod of claim 5, wherein the one or more N-halamine biocidal compoundscomprises the formula 1, 2, 3, 4, 5, 6, 7, 8 or combinations thereof:

wherein X, X¹, X², X³ and X⁴ are individually a Hydrogen, a halogen, analkyl, an alkylene, an alkenyl, an alkynyl, an aryl, an alkoxy, analkylcarbonyl, an alkylcarboxyl, an amido, a carboxyl, or a hydroxyl; nand m are individually integers between 0 and 1000; R¹ to R¹⁰ areindependently hydrogens, halogens, one or more C₁ to C₄₀ alkyl, C₁ toC₄₀ alkylene, C₁ to C₄₀ alkenyl, C₁ to C₄₀ alkynyl, C₁ to C₄₀ aryl, C₁to C₄₀ alkoxy, C¹ to C₄₀ alkylcarbonyl, C¹ to C₄₀ alkylcarboxyl, C¹ toC₄₀ amido, C₁ to C₄₀ carboxyl, a hydroxyl or combinations thereof. 10.The method of claim 5, further comprising the step of rechargingantimicrobial article by the addition of one or more halogens.
 11. Themethod of claim 5, wherein the target material comprise a polymer,organic material, inorganic material or combinations and mixturesthereof.
 12. The method of claim 5, wherein the rechargeableantimicrobial anti-biofilm article comprises plastics, rubbers, fibers,woods, paints, coatings, nanoparticles, glass, ceramics, resins, epoxiesor combinations and mixtures thereof, wherein the antimicrobialanti-biofilm article is rechargeable.
 13. A method of reducing theformation of biofilms on a surface comprising the steps of: adding oneor more N-halamine biocidal compounds to a target material; andprocessing the target material into an article, wherein the one or moreN-halamine biocidal compounds reduce the formation of biofilms on asurface of the article.
 14. The method of claim 13, wherein the one ormore N-halamine biocidal compounds comprises3-substituted-1-N-halo-5,5-disubstituted-hydantoin;3,3′-bissubstituted-1,1′-N-halo-5,5,5′5′-substituted-2,2′,4,4′-imidazolidinedione;1,3,8-Triaza-3-substituted-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decane;3,3′-disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,8,8′N-halo-2,4-dione;8,8′-disubstitued-bis(7,7,9,9-substitued)-1,3,8-Triazaspiro[4.5]decane-1,1′,3,3′N-halo-2,4-dione;Vinyl chloride-co-3-vinyl-N-halo-5,5-disubstituted hydantoin; Vinylchloride-co-3-vinyl-1,3,8-Triaza-7,7,9,9-substituted-1,8-N-halo-2,4-dioxospiro[4.5]decane,1,3-bis(hydroxylmethyl)-5,5-dimethylhydantoin,1-chloro-3-ethyl-5,5-dimethylhydantoins,1-chloro-3-dodecyl-5,5-dimethylhydantoin,1-chloro-3-octadecyl-5,5-dimethylhydantoin,1-chloro-3-docosyl-5,5-dimethylhydantoin,7,7,9,9-tetramethyl-3-hexyl-1,3,8-triazaspiro[4,5]decane-2,4-dione,7,7,9,9-tetramethyl-3-octadecyl-1,3,8-triazaspiro[4,5]decane-2,4-dione,7,7,9,9-tetramethyl-3-dodecyl-1,3,8-triazaspiro[4.5]decane-2,4-dione,7,7,9,9-tetramethyl-3-stearyl-1,3,8-triazaspiro[4,5]decane-2,4-dione,7,7,9,9-tetramethyl-3-octadecyl-1,3,8-triazaspiro[4.5]decane-2,4-dioneand mixtures thereof.
 15. The method of claim 13, further comprising thestep of regenerating the activity of the one or more N-halamine biocidalcompounds by exposing the one or more N-halamine biocidal compounds to ahalogen source.
 16. The method of claim 13, wherein the articlecomprises plastics, rubbers, fibers, woods, paints, coatings,nanoparticles, semiconductor materials, resins, epoxies paints, stains,inorganic materials or combinations thereof.
 17. The method of claim 13,wherein the one or more N-halamine biocidal precursors comprises one ormore structures of the formula 1, 2, 3, 4, 5, 6, 7, 8 or combinationsthereof:

wherein X, x¹, X², X³ and X⁴ are individually a Hydrogen or a halogen,an alkyl, an alkylene, an amino, an alkynyl, an alkoxy; n and m areindividually integers between 0 and 1000; R¹ to R¹⁰ are independentlyhydrogens, halogens, one or more C₁ to C₄₀ alkyl, C₁ to C₄₀ alkylene, C₁to C₄₀ alkenyl, C₁ to C₄₀ alkynyl, C₁ to C₄₀ aryl, C₁ to C₄₀ alkoxy, C₁to C₄₀ alkylcarbonyl, C₁ to C₄₀ alkylcarboxyl, C₁ to C₄₀ amido, C¹ toC₄₀ carboxyl, or combinations thereof.
 18. A biofilm-controllingN-halamine biocidal composition that provides photo and thermalstability comprising: one or more 3 to 10 membered rings comprising oneor more nitrogen heteroatoms, wherein one or more halogen associate withthe one or more nitrogen heteroatoms and control biofilm growth andprovide photo and thermal stabilization effects.
 19. Abiofilm-controlling and photo and thermal stabilizing additivecomprising: a sterically hindered N-halo-amine with a molecular weighthigher than 200 g/mol, wherein the composition provides anti-biofilm andthermal and photo stabilizing function.
 20. The composition of claim 19,wherein the sterically hindered N-halo-amine comprises.
 21. Thecomposition of claim 19, wherein the sterically hindered N-halo-aminecomprises Bis(N—X-2,2,6,6-tetramethyl-4-piperidyl)sebacate;2,2,6,6-tetramethyl-N-chloro-4-piperidinyl;Poly[[6-[(1,1,3,3-tetramethylbutyl)amino]-s-triazine-2,4-diyl]-N—X-[(2,2,6,6-tetramethyl-4-piperidyl)imino]-hexamethylene-[(2,2,6,6-tetramethyl-4-piperidylimino]];N—X-[(4-piperidyl)alkyl formate];Poly[(6-morpholino-s-triazine-2,4-diyl)-N—X-[2,2,6,6-tetramethyl-4-piperidyl]imino]-hexamethylene[(2,2,6,6-tetramethyl-4-piperidyl)imino]];3-Dodecyl-N-chloro-(2,2,6,6-tetramethyl-4-piperidinyl)succinimide;2,2,4,4-Tetramethyl-N—X-7-oxa-3,20-diazadispiro[5.1.11.2]-heneicosan-21-one;D-Glucitol,1,3:2,4-bis-O-(N-chloro-2,2,6,6-tetramethyl-4-piperidinylidene);1,1′-ethylenebis(N—X-3,3,5,5-tetramethyl-piperazinone);N—X-2,2,4,4-tetramethyl-7-oxa-20-(oxiranylmethyl)-3,20-diazadispiro[5.1.11.2]henicosan-21-one;1,2,3,4-Butanetetracarboxylic acid, polymer withb,b,b′,b′-tetramethyl-2,4,8,10-tetraoxaspiro[5.5]undecane-3,9-diethanol,N—X-2,2,6,6-tetramethyl-4-piperidinyl ester;Poly[oxy[methyl[3-[N—X—(2,2,6,6-tetramethyl-4-piperidinyl)-oxy]propyl]silylene]];1,1′,1″-[1,3,5-Triazine-2,4-6-triyltris[(cyclohexylimino)ethylene]]tris(N-chloro-3,3,5,5-tetramethyl-piperazinone);and mixtures and combinations thereof, wherein X is Cl, Br or acombination thereof.